Method of treating infections, diseases or disorders of nail unit

ABSTRACT

Methods for the subungual treatment of diseases or disorders of the nail unit including infections, especially fungal infections, and nail psoriasis involving the toenails and fingernails are described. The methods provide a technique for placement of a drug-containing composition subungually with reduced risk of hematoma formation and improved patient comfort.

CROSS-REFERENCE TO RELATED APPLICATIONS

This application is a continuation of U.S. application Ser. No.14/201,320, filed Mar. 7, 2014, which claims the benefit of U.S.Provisional Application No. 61/784,065, filed Mar. 14, 2013 and of U.S.Provisional Application No. 61/877,229, filed Sep. 12, 2013, eachincorporated is herein by reference in its entirety.

TECHNICAL FIELD

The subject matter described herein relates to compositions and tomethods for the subungual (under the nail) treatment of diseases ordisorders including infections, especially fungal infections, of thetoenails and fingernails (onychomycosis) and nail psoriasis.

BACKGROUND

Nail infections are common conditions of the nail. Onychomycosis, afungal infection of the nail bed, matrix, or nail plate, is the mostcommon nail infection. The primary clinical features of onychomycosisare distal onycholysis (separation of the nail plate from the nail bed),subungual hyperkeratosis, and a dystrophic, discolored nail. Patientsafflicted with onychomycosis are usually embarrassed by their naildisfigurement, but the infection is more than a cosmetic problem. It cansometimes limit mobility and indirectly decrease peripheral circulation,thereby worsening conditions such as venous stasis and diabetic ulcers.Fungal infections of the nail can also spread to other areas of the bodyand potentially to other persons. The fungal infection can be caused bydermatophytes (e.g., Trichophyton rubrum and T. mentagrophytes), but mayalso be due to infection by Candida species or nondermatophyte moldssuch as Aspergillus species, Scopulariosis brevicaulis, Fusariumspecies, and Scytalidium species.

Currently, oral antifungal agents are the mainstay of treatment foronychomycosis. For example, Sporonox®. capsules (itraconazole) (JanssenPharmaceutica Products, L.P., Titusville, N.J. and Ortho BiotechProducts, L.P., Raritan, N.J.), Lamisil® tablets (terbinafinehydrochloride) (Novartis Pharmaceuticals, East Hanover, N.J.), Diflucantablets and fluconazole (Pfizer, New York, N.Y.) are commonly prescribedantifungal agents. However, these oral antifungal products areassociated with many minor systemic side effects such as headaches,stomach upset, skin rashes, and photosensitivity, as well as serioussystemic side effects such as heart failure and liver failure. Althoughoral antifungal therapy is preferred, risk of the serious side effectsoften outweighs therapeutic benefit, and drug-drug interactions are aproblem for many patients. The prolonged treatment regimen of one dosedaily for at least three months, or once weekly for nine to twelvemonths also leads to poor patient compliance with oral antifungaltherapy.

Topical therapy with antifungal agents is an alternative to oraltherapy, and a topical solution, Penlac® nail lacquer (ciclopiroxsolution, 8%) (Dermik Laboratories, Berwyn, Pa.), is approved by the FDAfor the topical treatment of mild to moderate onychomycosis. However,the topical mode of administration is seldom effective to treat morethan mild nail unit infections because the active agent is unable toeffectively penetrate the nail. Topical therapy accompanied by chemicalor physical abrasion of the nails has also been largely unsuccessful.Topical antifungal therapy usually also involves daily application tothe nails for several months, and thus, also poses a compliance problem.Topical nail treatment typically precludes the use of nailcosmetics/polish that otherwise would be used to camouflage the diseasedand/or disfigured nail plate.

Psoriasis is estimated to affect approximately 2% of the population. Asmany as 50% of psoriasis patients may have nail involvement (psoriaticnail disease or nail psoriasis) with a lifetime incidence in psoriasispatients reaching 80-90%. Nail disease without cutaneous involvement ispresent in an estimated 5-10% of psoriasis patients. Common features ofnail psoriasis include pitting (present in an estimated 68% of affectedpatients), onycholysis (in 67%), subungual hyperkeratosis (in 25%), oildrop signs (discoloration), crumbling of the nail plate, and splinterhemorrhage, the latter four of these being associated with nail bedinvolvement. In addition to the obvious cosmetic problem, many patientswith nail psoriasis, especially when the fingernails are involved,suffer pain, loss of manual dexterity, and diminished sensation oftouch. Onychomycosis may additionally be present with nail psoriasis.

Medications that have been used with varying degrees of success intreating nail psoriasis include corticosteroids (e.g. betamethasonedipropionate, clobetasol, triamcinolone acetonide), vitamin D analogs orderivatives (e.g. calcipitriol, calcipotriene, tacalcitol, calcitriol),retinoids (tazarotene, etretinate), biologicals (e.g. infliximab,adalimumab), antimetabolite drugs such as 5-fluorouracil, andimmunosuppressants/calcineurin inhibitors such as cyclosporine andtacrolimus. Topical application of medications has limited use as themedication may not penetrate the nail plate to reach the affected area.Specifically for psoriasis involving the nail bed, where onycholysis andsubungual hyperkeratosis are prominent, topically applied antipsoriaticagents have limited transungual penetration into the affected nail bed.Corticosteroid injections into the nail bed have been used with varyingresults.

Overall, treatment of diseases of the nail unit remains challenging andthere remains a continuing need for the development of effective meansfor the treatment of diseases of the nail unit, particularly diseasesthat call for delivery of active ingredient to the nail unit forsustained periods of time. An additional need is for treatments thatminimize pain.

The foregoing examples of the related art and limitations relatedtherewith are intended to be illustrative and not exclusive. Otherlimitations of the related art will become apparent to those of skill inthe art upon a reading of the specification and a study of the drawings.

BRIEF SUMMARY

The following aspects and embodiments thereof described and illustratedbelow are meant to be exemplary and illustrative, not limiting in scope.

In one aspect, a method for treating a disease or disorder of the nailunit is provided. In one embodiment, the disorder of the nail unit is aninfection such as a fungal infection, such as onychomycosis. The methodcomprises providing a device comprised of an applicator and acomposition comprising an active agent such as an antifungal agent or ananti-psoriatic agent; inserting the applicator subungually; anddepositing the composition subungually.

In one embodiment, the applicator comprises a needle and the compositionis disposed in the needle tip. In embodiments, the needle has a beveltip and the composition is disposed at least partially in the bevel tip.

In another embodiment, the applicator comprises a cannula, which mayhave a blunt distal end or tip. In embodiments, the composition isdisposed in the cannula, which will have at least one opening fordepositing the composition. In another embodiment, the applicatorcomprises a cannula and a needle that is sized to have the same orhigher (finer) gauge than the cannula. In other embodiments, thecomposition is deposited subungually from the needle, while the cannularemains at least partially inserted subungually. In other embodiments,the composition is deposited from the needle portion of theneedle-cannula applicator after the cannula is withdrawn from itssubungual position. In other embodiments, the composition is depositedfrom the needle portion of the needle-cannula applicator simultaneouslywith withdrawal of the cannula from its subungual position.

In another embodiment, the method further comprises, prior to insertingthe applicator, placing the needle or cannula on the exterior surface ofthe nail and placing a depth marker on the needle or cannula to mark thedesired insertion depth. In one embodiment, the needle or cannula isplaced on the exterior surface of the nail such that a distal end of thebevel tip or end touches a distal edge of the lunula, and the depthmarker is placed on the needle or cannula where it aligns with thehyponychium.

In a further embodiment, the method further comprises, prior toinserting the applicator, placing the needle or cannula on the exteriorsurface of the nail such that a distal end of the needle or the cannulaapproximately aligns with or extends just beyond the most proximal pointof a fungal infection or other disease indication in the nail or thenail bed, and a depth marker is placed on the needle or cannula where italigns with the hyponychium.

In still another embodiment, the step of inserting comprises insertingthe needle or cannula past the hyponychium and between the nail plateand the nail bed at least until the depth marker is aligned with thehyponychium. In some embodiments, the step of inserting the needle orcannula comprises inserting above the hyponychium and under the nailplate, or through the hyponychium and under the nail plate. In someembodiments, the insertion is done at the point of highest curvaturemidway between the lateral fold and midline of the nail.

In yet another embodiment, the step of inserting comprises inserting theneedle or cannula at a position between the nail fold and a longitudinalmidline of the nail plate.

In other embodiments, the method further comprises after inserting andprior to depositing, withdrawing the needle or cannula to a regionbetween the distal edge of the lunula and the hyponychium.

In another embodiment, the steps of providing, inserting and depositingare repeated to place a subsequent composition subungually. Thesubsequent composition may be the same as or different than a firstcomposition deposited. The subsequent composition may be deposited at asame or different site than the first composition deposited.

In another embodiment, the applicator comprises a cannula having a bluntend and a needle. The inserting step comprises inserting the cannulapast the hyponychium and between the nail plate and the nail bed to adesired depth to create a channel or space in the subungual space.Inserting the cannula past the hyponychium can include, in someembodiment, inserting the cannula above the hyponychium or through thehyponychium by piercing the hyponychium. The cannula is typicallywithdrawn and the needle is then inserted at least partially into thechannel formed by the cannula to a desired depth.

In one embodiment, the composition is a solid composition, sometimesreferred to herein as an ‘implant’, or is a semi-solid composition or acomposition in the form of a solution or liquid. In embodiments, thecomposition comprises an antifungal agent or an anti-psoriatic agent.

In one embodiment, the solid or semi-solid composition is comprised of abiodegradable polymer.

In another embodiment, the biodegradable solid composition or implant iscomprised of a polymer having a melting temperature (Tm) greater thanthe temperature of the nail bed.

In another embodiment, the antifungal agent is released by erosion ordegradation of the polymer over a period of at least about 2 weeks,alternatively over a period of at least about 4 weeks.

In one embodiment, the antifungal agent is released to provide aninitial burst of active agent followed by a period of extended releaseof active agent. In one embodiment, the period of extended releasecomprises at least 10 days, preferably 2 weeks, more preferably at least4 weeks.

In another embodiment, the composition is comprised of polyethyleneglycol with a molecular weight of between 1,000-8,000 Daltons. In stillanother embodiment, the composition is comprised of the antifungal agentdistributed within a polyethylene glycol with a molecular weight ofbetween 2,000-5,000 Daltons. In yet another embodiment, the compositioncomprises less than about 40 weight percent polyethylene glycol. Inanother embodiment, the composition comprises at least about 60 weightpercent active agent. In another embodiment, the composition comprisesbetween about 65-80 weight percent active agent.

In one embodiment, the antifungal agent is terbinafine hydrochloride oris terbinafine free base. In another embodiment, the antifungal agent isnaftifine. In an embodiment, the anti-psoriatic agent is selected fromthe group consisting of steroids, vitamin A or derivatives, vitamin D orderivatives, calcineurin inhibitors and an anti-metabolite.

In other embodiments, the composition comprises a liquid carrier. In oneembodiment, the liquid carrier is a silicone oil.

In one embodiment, the liquid composition (solution or suspension)comprises between about 0.5-5 weight percent anti-fungal agent. In apreferred embodiment, the anti-fungal agent is terbinafine hydrochlorideor terbinafine free base. In another embodiment, the anti-fungal agentis naftifine.

In another embodiment, the active agent is an anti-psoriatic agent. Inembodiments, the anti-psoriatic agent is selected from steroids, vitaminA or derivatives, vitamin D or derivatives, a calcineurin inhibitor, andan anti-metabolite.

In one embodiment, the composition is an immediate release compositionfor release of the active agent. In embodiments, the compositionprovides for release of the active agent within 10 minutes to 2 hoursafter administration.

In a further embodiment, the composition is a delayed releasecomposition for release of the active agent. In some embodiments, thecomposition provides for release of the active agent for days to weeksafter administration. In additional embodiments, the compositionprovides for release of the active agent for 2-4 weeks afteradministration.

In an embodiment, the disease or disorder of the nail unit isonychomycosis exhibiting lateral edge nail involvement.

In another aspect, a dosing regimen for treating a disease or disorderof the nail unit is provided. The regimen comprises administeringsubungually a first device and a second device, the first and seconddevices each comprised of a biodegradable polymeric matrix and an activeagent dispersed in the matrix. Then, a period of time is allowed to passand a third device and optionally a fourth device is/are administered,the third device and optional fourth device are comprised of abiodegradable polymeric matrix and an active agent dispersed in thematrix. The period of time that passes achieves release of the activeagent from the matrix at a rate to maintain a concentration of activeagent in a substantial portion of the nail bed above the minimuminhibitory concentration; and the administering comprises depositing thedevices at a position between a lateral nail fold and a longitudinalmidline of the nail plate. In an embodiment, the disease or disorder ofthe nail unit is onychomycosis and the active agent is an anti-fungalagent. In another embodiment, the disease or disorder of the nail unitis nail psoriasis and the active agent is an anti-psoriatic agent. In afurther embodiment, the disease or disorder of the nail unit exhibitslateral edge nail involvement.

In one embodiment, the steps of administering comprise placing a needleor cannula on the exterior surface of the nail plate such that a distalend of the needle or cannula touches a distal edge of the lunula, andplacing a depth marker on the needle where it aligns with thehyponychium.

In another embodiment, the step of administering comprises placing aneedle or cannula on an exterior surface of the nail such that a distalend of the needle or cannula approximately aligns with or extends justbeyond a proximal point of a fungal infection in the nail, and placing adepth marker on the needle where it aligns with the hyponychium. In yetanother embodiment, the step of administering comprises placing a needleor cannula on an exterior surface of the nail such that a distal end ofthe needle or cannula approximately aligns with or extends just beyond aproximal point of disease in the nail, and placing a depth marker on theneedle where it aligns with the hyponychium.

In one embodiment, the step of administering comprises inserting theneedle or cannula past the hyponychium and between the nail plate andthe nail bed until the depth marker is aligned with the hyponychium.

In other embodiments, the step of administering comprises withdrawingthe needle or cannula to a region between the distal edge of the lunulaand the hyponychium.

In yet another embodiment, waiting a period of time comprises waiting atleast about two weeks, alternatively in another embodiment, waiting aperiod of time comprises waiting at least about four weeks.

In a further embodiment, the dosing regimen further comprises insertinga cannula past the hyponychium and between the nail plate and the nailbed to create a channel or space in the subungual space prior toadministering the active agent.

In addition to the exemplary aspects and embodiments described above,further aspects and embodiments will become apparent by reference to thedrawings and by study of the following descriptions.

Additional embodiments of the present methods, regimens, devices,systems, compositions, and the like, will be apparent from the followingdescription, drawings, examples, and claims. As can be appreciated fromthe foregoing and following description, each and every featuredescribed herein, and each and every combination of two or more of suchfeatures, is included within the scope of the present disclosureprovided that the features included in such a combination are notmutually inconsistent. In addition, any feature or combination offeatures may be specifically excluded from any embodiment of the presentinvention. Additional aspects and advantages of the present inventionare set forth in the following description and claims, particularly whenconsidered in conjunction with the accompanying examples and drawings.

BRIEF DESCRIPTION OF THE DRAWINGS

FIGS. 1A-1F illustrate a procedure for inserting an implant subunguallyin accord with one embodiment.

FIGS. 2A-2F illustrate another procedure for inserting an implant inaccord with another embodiment.

FIGS. 3A-3D illustrate another procedure for inserting an implant inaccord with another embodiment.

FIGS. 4A-4B are X-ray images showing subungual insertion of a cannula(FIG. 4A) and a needle (FIG. 4B).

DETAILED DESCRIPTION I. Definitions

Various aspects now will be described more fully hereinafter. Suchaspects may, however, be embodied in many different forms and should notbe construed as limited to the embodiments set forth herein; rather,these embodiments are provided so that this disclosure will be thoroughand complete, and will fully convey its scope to those skilled in theart.

Where a range of values is provided, it is intended that eachintervening value between the upper and lower limit of that range andany other stated or intervening value in that stated range isencompassed within the disclosure. For example, if a range of 1 μm to 8μm is stated, it is intended that 2 μm, 3 μm, 4 μm, 5 μm, 6 μm, and 7 μmare also explicitly disclosed, as well as the range of values greaterthan or equal to 1 μm and the range of values less than or equal to 8μm.

As used in this specification, the singular forms “a,” “an,” and “the”include plural referents unless the context clearly dictates otherwise.Thus, for example, reference to a “polymer” includes a single polymer aswell as two or more of the same or different polymers, reference to an“excipient” includes a single excipient as well as two or more of thesame or different excipients, and the like.

II. Method of Treatment

In one aspect, a method for treating infection disease or disorder ofthe nail unit is provided. The method comprises providing a devicecomprised of an applicator and a composition comprising a therapeutic oractive agent; inserting the applicator subungually; and depositing thecomposition subungually. Before describing the method and implantationprocedure in detail, it is useful to provide information on the nailunit.

The human nail comprises several parts including, but not limited to,the nail matrix, the nail bed, the nail plate, the nail folds, thehyponychium, and the cuticle. The nail plate (fingernail or toenail) isproduced by the matrix and progresses toward the tip of the fingers ortoes as new plate is formed. The primary function of the nail plate isto protect the underlying digit. The cutaneous tissue framing the nailunit, and which invaginates proximal and lateral to the nail plate, isreferred to as the nail folds. The nail matrix is located beneath theproximal nail fold, and is the germinative portion of the nail unit thatproduces the nail plate. The lunula is the whitish crescent-shaped baseof the nail and is the visible part of the nail matrix. The eponychium(or cuticle) is an outgrowth of the proximal fold, situated between theskin of the digit and the proximal end of the nail plate, fusing thesestructures together. The hyponychium is epithelial tissue locatedbeneath the distal end of the nail plate at the junction between thefree edge of the nail plate and the skin of the digit (finger or toe).It forms a seal that protects the nail bed. The nail bed is the layer oftissue underneath the nail between the lunula and the hyponychium.

With reference now to FIGS. 1A-1F, a method of treatment wherein acomposition comprising a therapeutic or active agent is administeredsubungually is illustrated. A device 10 is comprised of an applicator 12and a composition 14 (seen best in FIGS. 1E-1F). The applicator can takemany forms, and the embodiment shown in the drawing is merely exemplary.In this embodiment, applicator 12 is comprised of a needle 16 with adistal tip or end 18. In another embodiment, the applicator 12 iscomprised of a cannula with a distal tip or end 18. A cannula for use inthe present methods typically has a substantially blunt or rounded endfor atraumatic introduction of the cannula under the nail plate. Oneexemplary cannula is a dermatological cannula such as a micro-cannulaused for filler injections. One particular cannula is the micro-cannulaavailable from Inex. A cannula alone may be used for subungual deliveryof the therapeutic or active agent. Use of a cannula is particularlyuseful where the disease or disorder involves onycholysis or wheresubungual debris has accumulated as it is not necessary to pierce thenail unit for delivery of the therapeutic or active agent. In yetanother embodiment, the applicator 12 is comprised of a cannula and aneedle. The distal tip of the needle and/or the cannula is dimensionedto contain or hold a composition, particularly when the composition is asolid or semi-solid composition as discussed below. In embodiments wherethe composition is in the form of a flowable solution (which may afterimplantation become semi-solid or solid), the needle/cannula and distaltip are dimensioned to permit dispensing of the flowable compositionwith a force applied by a user. The composition in the embodiment shownin FIGS. 1A-1F is a solid or semi-solid implant, for purposes ofillustration, and is contained in the distal tip of the needle orcannula prior to insertion and/or implantation subungually. In someembodiments, the distal tip of the needle is beveled, and the implant(e.g., a solid composition) is situated in the beveled tip. In otherembodiments, the implant is situated in the distal tip of the cannula.In one embodiment, the device as provided to the user comprises thecomposition situated in the distal tip of the needle or cannula. Inother embodiments, the composition is provided with the device in aseparate packaging unit from the applicator, and the user prior toimplantation situates the solid composition into the distal tip of theneedle or cannula, or, more generally, situates the solid compositioninto the applicator.

The applicator may also comprise a handling member, such as thefinger-tip hub 20 of applicator 12. A proximal end 22 of needle orcannula 16 extends into the handling member, and in one embodiment issecured within the handling member. The applicator may also comprise astylet or plunger 24. Stylet 24 is dimensioned to be insertable into theproximal end of needle or cannula 16, and to travel a distance in thebore of needle or cannula 16 sufficient to dispense an implant situatedin the needle or cannula. The stylet may optionally include a handle,such as handle 26, at its proximal end to ease handling by a user.

Use of the applicator is described below with reference to theembodiment where the applicator comprises a needle. It will beappreciated that the embodiment where the applicator comprises a cannulais equally contemplated unless otherwise noted. It will further beappreciated that the description of the applicator below applies equallyto a cannula and needle in the embodiment where a cannula is subunguallyinserted prior to insertion of a needle. Use of the applicator isfurther described below with reference to the embodiment where thedisorder or disease of the nail unit is an infection. It will beappreciated that use of the applicator as described is equallyapplicable to other disorders or diseases of the nail unit unlessotherwise noted.

With reference to FIG. 1A, administration of the composition subunguallycomprises placing the needle on the top of the nail plate such that thedistal tip of the needle is approximately aligned above or touches thedistal edge of the lunula. When aligning the distal tip with the distaledge of the lunula, the needle is placed on the top (or exteriorsurface) of the nail plate approximately one-third of the way across thenail unit, as depicted in FIG. 1A. It will be appreciated that theneedle may be placed more or less than one-third of the way across thenail unit depending on the subject and desired treatment. Statedalternatively, the needle is placed on the exterior nail plate in aregion defined by a longitudinal (intending a line extending from thefree margin or distal edge of the nail plate to the eponychium) midlineof the nail plate and a lateral nail fold. For convenient reference, thelongitudinal line defined by placement of the needle, as just described,is referred to as the “needle placement line.” In one embodiment, theneedle placement line is in the region defined by the longitudinalmidline and a lateral nail fold where the radius of curvature isgreatest. In general, the optimal site(s) for individualized insertionshould be determined. The needle placement line may then be determinedby the optimal insertion site(s). Generally, optimal sites have reducedadherence of the nail plate to the nail bed to allow for easierinsertion of the needle and/or cannula. Thus, onycholytic areas tend tobe optimal for insertion. In other embodiments, areas exhibitingsubungual hyperkeratotic areas, especially after debridement of thearea, may be optimal insertion site(s). In other embodiments, the areaof the nail plate having the greatest radius of curvature between thenail plate midline and the lateral folds. With the needle in the needleplacement line, an indicator mark along the needle shaft where it meetsthe hyponychium is noted. This may involve noting which of a series ofpre-made indicator marks on the needle aligns with the hyponychium or itmay involve the user making a mark, such as indicator mark 28 in FIGS.1A-1E. As will be described, the indicator mark serves as a depth guidefor inserting the needle subungually (and depositing the compositioninto nail bed tissue or into a subungual space). It will be appreciatedthat the indicator mark 28 may indicate an insertion depth that is lessthan or greater than the distal edge of the lunula.

With reference to FIG. 1B, the needle is placed at a desired insertionpoint, indicated at 30 in FIG. 1B. The insertion point, in oneembodiment, is at the level of the hyponychium along the needleplacement line. This is illustrated in FIG. 1B, where the distal tip ofthe needle is positioned at the hyponychium along the needle placementline (see in FIG. 1A). As seen in FIG. 1C, the distal tip of the needleis inserted past the hyponychium, under the nail plate and into thespace above the nail bed and under the nail plate. In embodiments, theneedle may be inserted at least partially into the nail bed. The needleis inserted until the indicator mark 28 is aligned with the hyponychium(FIG. 1C).

FIG. 1D illustrates an optional step in the implantation process. Inthis optional step, the needle, after inserting such that the indicatormark is aligned with the hyponychium and prior to depositing thecomposition, is withdrawn to a region between the distal edge of thelunula and the hyponychium. More particularly, the needle is withdrawn adistance of 0.5-5 mm, alternatively a distance of 0.5-4 mm, or 0.75-4 mmor 1-4 mm, to create a space 32 between the nail plate and the nail bed.The composition is then deposited into the space created by insertion ofthe needle. When the composition is a solution, liquid, or semi-solid,the composition may be deposited as the needle is withdrawn (retrogradeinjection or insertion). Depositing the composition into the spacecreated by the needle/cannula reduces the force required to deposit thecomposition.

Then, as shown in FIG. 1E, stylet 24 is engaged to move in a directionshown by arrow 34, from the proximal end of the needle to the distal tipof the needle, to deposit composition 14 from the needle into the nailbed or into a subungual space between the nail plate and the nail bed,just distal to the lunula. The needle is then removed, as shown in FIG.1F, leaving the composition in the nail unit.

Another embodiment of the implantation process is shown in FIGS. 2A-2F.Elements in FIG. 2 that are similar to elements in FIG. 1 are given thesame numerical indicator for convenience. In the embodiment of FIG. 2,the location of the infection in the nail unit, rather than the lunula,is used as a guide for determining the indicator mark. It will furtherbe appreciated that a further location on the nail plate may be used asa guide for determining the indicator mark. This approach is useful, forexample, if the infection, or other disease or disorder, makes thelunula or other part of the nail bed not visible or having limitedvisibility, however, use of this approach is not so limited. Withreference to FIG. 2A, a human finger and nail unit are shown, where thenail unit is infected with a fungus. The fungus causes discoloration,thickening and/or disfiguring of the nail plate, as denoted at 40 inFIG. 2A. Device 10, comprised of an applicator 12 and a composition 14,is provided, and if initially provided in a package, is removed from thepackaging.

Administration of the implant subungually comprises placing the needleon the top of the nail plate such that the distal tip of the needle isapproximately aligned with or extends just beyond a proximal point offungal infection in the nail, as illustrated in FIG. 2A. When aligningthe distal tip with a proximal point of fungal infection in the nail,the needle is placed on the top (or exterior surface) of the nail plateapproximately one-third of the way across the nail unit, as depicted inFIG. 2A. Stated alternatively, the needle is placed on the exterior nailplate in a region defined by a longitudinal (intending a line extendingfrom the free margin or distal edge of the nail plate to the eponychium)midline of the nail plate and a lateral nail fold—the “needle placementline.” In one embodiment, the needle placement line is in the regiondefined by the longitudinal midline and a lateral nail fold where theradius of curvature is greatest. Upon correct placement of the needle,an indicator mark 28 along the needle shaft where it meets thehyponychium is noted. It will be appreciated that administration of theimplant subungually may be accomplished without prior marking of theneedle or cannula, especially where the nail unit allows sufficientvisibility for subungual insertion. It will further be appreciated thatother methods of visualizing the cannula and/or needle may be usedincluding, but not limited to ultrasound and x-ray imaging.

With reference to FIG. 2B, the needle is placed at a desired insertionpoint, indicated at 30 in FIG. 2B. The insertion point, in oneembodiment, is at the level of the hyponychium along the needleplacement line. This is illustrated in FIG. 2B, where the distal tip ofthe needle is positioned at the hyponychium along the needle placementline (see in FIG. 2A). As seen in FIG. 2C, the distal tip of the needleis inserted past the hyponychium, under the nail plate and into thesubungual space between the nail plate and the nail bed. The needle isinserted until the indicator mark 28 is aligned with the hyponychium(FIG. 2C). In some patients, the disease or disorder such as aninfection results in onycholysis, creating a space in the nail unitwhere the composition can be placed. In other patients, subungual debrisis present, and debridement of the subungual debris creates a path orspace for insertion and placement of a composition. Accordingly, themethod described herein contemplates identifying for an individualpatient the optimal insertion point of the needle, placement of thecomposition into the nail bed or a subungual space, and the composition.In some patients, the desired insertion point is at the point ofgreatest radius of curvature in the region defined by the longitudinalmidline of the nail plate and a lateral nail fold. In other patients,the desired insertion point is in the region defined by the longitudinalmidline of the nail plate and a lateral nail fold where onycholysis hasoccurred or where subungual debris has accumulated and can be removed.

Then, as shown in FIG. 2D, stylet 24 is engaged to move in a directionshown by arrow 34, from the proximal end of the needle to the distal tipof the needle, to deposit composition 14 from the needle into the nailbed or into a subungual space between the nail plate and the nail bed,with a proximal edge of the composition at the approximate proximal edgeof the site of infection. In another embodiment, the composition isdeposited from the needle into the nail bed or into a subungual spacewithout the use of a stylet. In one embodiment, the composition isdeposited by pushing or injecting the composition through the needle tothe desired site. The needle is then removed, as shown in FIG. 2E,leaving the composition in the nail unit at the desired location.

It will be appreciated that the steps described above for implantationof a composition subungually can be repeated to deposit a secondcomposition and, if desired, subsequent compositions in the nail unit.It will further be appreciated that the second and any subsequentcompositions may be the same or different than the first compositiondeposited. FIG. 2F depicts an infected nail unit with two solidcompositions or implants. It will further be appreciated that, dependingon the degree of onycholysis and/or subungual hyperkeratosis, wherepresent, a fanning technique may be used to expand the space into whichthe composition is dispensed. It will also be appreciated that after theimplantation procedure, pressure or a temperature treatment can beapplied to the treatment site.

In one embodiment as shown in FIGS. 3A-3D, a cannula is used to create asubungual channel into which the active agent may be delivered. As shownin FIG. 3A, a blunt or rounded cannula is subungually inserted tocreate, define, or enlarge a subungual channel into which thecomposition may be administered. The cannula 15 is inserted into thesubungual space as described above for the needle. The cannula isremoved leaving a space or channel 32 in the subungual space (FIG. 3B).Using a cannula with a blunt tip or end may be useful to minimize orreduce pain and trauma as compared to subungual insertion of a needle. Aneedle or cannula 17 having the same or a finer gauge is then insertedinto the channel 32 formed by the cannula 15 (seen in FIG. 3C). Theneedle may be inserted further into the subungual space than the depthof the channel if desired. The composition, product or implant 14 isadministered into the channel 32 created by the blunt end cannula withthe needle and the needle is removed (FIG. 3D). In another embodiment aliquid or semi-solid composition may be administered from an opening inthe cannula. It will be appreciated that where a composition isadministered from the cannula, administration of a same or differentcomposition may be administered from a needle as described above.Although the composition may be administered as the cannula is inserted,it is preferable for the composition to be administered as the cannulais withdrawn (e.g. in retrograde fashion) to facilitate deposition ofthe composition with the cannula. The presence of a space in advance ofthe cannula/needle distal end avoids exertion of additional force orpressure to expel the composition from the cannula/needle.Administration of the composition from the cannula may further be inaddition to administration of the same or a different composition fromthe needle.

As the cannula has a blunt end, it can be larger (lower gauge number)than the needle while minimizing or reducing pain and/or trauma. In anembodiment, the cannula and needle have the same gauge. In anotherembodiment, the needle has a finer (higher gauge number) than thecannula used to create, define or enlarge the subungual channel.

The methods described herein provide an approach for treatment that isindividualized for each patient. As described above, for each individualpatient the optimal insertion point of the needle is determined, basedon condition of the nail and extent of disease or infection. In somepatients, the insertion point is at the point of greatest radius ofcurvature in the region defined by the longitudinal midline of the nailplate and a lateral nail fold, and the depth of insertion is withrespect to the distal edge of the lunula or with respect to the proximaledge of the disease or infection. In other patients, the desiredinsertion point is in the region defined by the longitudinal midline ofthe nail plate and a lateral nail fold where onycholysis has occurred orwhere subungual debris has accumulated and can be removed, and the depthof insertion is with respect to the proximal edge of the disease orinfection or with respect to the distal edge of the lunula. The methodsare also individualized in that the composition administered can betailored, to be a solid, a semi-solid or a solution, or a combinationthereof, as well as immediate release or extended release compositions,or a combination thereof. In the methods, the composition is desirablyadministered into a subungual space, and not into a tissue of the nailunit, in one embodiment.

It will also be appreciated that the nail unit and/or digit of thepatient may be treated with one or more procedures, for example, with adisinfectant, an anesthetic to reduce pain, a hemostatic agent todecrease bleeding, or a keratolytic agent to facilitate deviceinsertion/drug delivery. In one embodiment, the treatment proceduredescribed herein is performed on a patient without anesthesia, local orsystemic. Treatment with another procedure(s) may be done prior to theinsertion procedure described herein, or may be done concurrent with theinsertion procedure, as would be the case where the composition to bedeposited subungually comprises a hemostatic agent or a keratolyticagent in addition to an antifungal agent. In one embodiment, a digitalblock is provided to the patient prior to inserting the cannula orneedle past the hyponychium and under the nail plate.

The method of treatment and identification of an optimal site fordepositing a composition subungually, described above, provides anunexpected advantage in reducing incidence of hematoma formation in thenail unit. It was found that the combination of the needle placementline and the indicator mark provide an accurate delivery protocol at aregion in the nail unit most receptive to the implant. Insertion of theneedle, and depositing the composition, along the line referred to aboveas the needle placement line, which is a line in a region defined by alongitudinal (intending a line extending from the free margin or distaledge of the nail plate to the eponychium) midline of the nail plate anda lateral nail fold, identifies a position in the nail unit that is morereceptive to perturbation than, for example, at the midline of the nail.In some embodiments, identifying the needle placement line also includesidentifying a point of greatest radius of curvature, of onycholysisand/or of the presence (and removal) of subungual debris, in the regionfor the needle placement line.

The nail plate may be intact, partially missing or otherwise compromised(e.g. damaged). In one embodiment, the nail of the subject sufferingfrom a nail unit infection has an intact or uncompromised nail plate,and the process described above is performed. In another embodiment, thenail of the subject suffering from a nail unit infection or otherdisease or disorder is more than ⅔ compromised, by visual inspection, bythe infection or other disease or disorder.

The method of treatment and identification of an optimal site fordepositing a composition subungually as described above provides anunexpected advantage of depositing the composition with low, minimal,reduced or no pain. In embodiments, the procedure may be performed withlittle or no anesthetic. As described in Example 3, a subject diagnosedwith onychomycosis affecting 75% of the nail length underwent twoprocedures involving subungual insertion of a needle or subungualinsertion of a needle preceded by subungual insertion of a blunt tipcannula. On the first day, a 25 gauge needle having a beveled tip wasinserted into the subungual space. The patient reported pain during theprocedure as a 0.6 on a scale of 0-10. Eighteen hours after theprocedure, the subject reported no residual pain from the firstprocedure. On day 2, an 18 gauge blunt tip cannula was subunguallyinserted 6.5 mm (FIG. 4A). The cannula was withdrawn and an 18 gaugeneedle was inserted into the channel formed by the cannula (FIG. 4B).The subject reported pain from the second procedure as a 0 on the painscale. Of note, the cannula and the needle as used in the secondprocedure was larger than the needle used in the first procedure (18gauge vs. 25 gauge). Insertion of a 25 gauge needle resulted in slightpain. Insertion of a larger (18 gauge) cannula and needle resulted in nopain. Thus, use of a cannula results in minimal pain from the procedureas compared to subungual insertion of a needle, even for a largerdiameter cannula. Nor did subungual insertion of a needle after thecannula result in increased pain as compared to insertion of the cannulaalone. As described in Examples 4-9, the pain involved with insertion ofa cannula and then insertion of a needle was similar or less than thepain involved with insertion of the cannula alone. As described inExample 6, even where the use of a cannula to create an initial channelin the subungual space requires anesthesia, subsequent access with acannula/needle may be achieved without anesthesia and with significantlyreduced pain. As described in Example 7, the methods described hereinallow for treatment of nails that are difficult to treat or may not betreatable with other methods of treatment. Without being limited as totheory, the use of a blunt tip for the cannula may allow for subungualinsertion of a larger instrument without trauma or minimal trauma to thenail bed. Further, subungual use of a blunt tip cannula followed bysubungual insertion of a needle for deposition of a composition isrelatively painless/incurs minimal pain.

A. Dosing Regimen

In another aspect, a dosing regimen for treating a disease or disorderof the nail unit is provided. In embodiments, a dosing regimen fortreating an infection such as a bacterial or fungal infection isprovided. In one particular embodiment, a dosing regimen for treatingonychomycosis is provided. In other embodiments, a dosing regimen fortreating psoriatic nail disease is provided. The regimen comprisesadministering subungually a first device and a second device, the firstand second devices each comprised of a biodegradable polymeric matrixand an antifungal agent dispersed in the matrix. Then, a period of timeis allowed to pass and a third device and optionally a fourth deviceis/are administered, the third device and optional fourth devicecomprised of a biodegradable polymeric matrix and a therapeutic oractive agent such as an antifungal agent dispersed in the matrix. Theperiod of time that passes achieves release of the therapeutic or activeagent from the matrix at a rate to maintain a concentration oftherapeutic or active agent in a substantial portion of the nail bedabove the minimum inhibitory concentration; and the administeringcomprises depositing the devices at a position between a lateral nailfold and a longitudinal midline of the nail plate.

In one embodiment of the dosing regimen, the implantation procedure setforth in FIG. 1, FIG. 2, or FIG. 3 is followed, to deposit the desirednumber of devices or compositions in a space between the nail plate andthe nail bed.

The period of time that lapses between administration of the first andsecond compositions and additional compositions can be about two weeks,four weeks, six weeks, eight weeks or twelve weeks. The period of timeis determined by several factors, such as the condition of the patient,the extent of the disease or infection, and the properties of thecomposition. It is preferred that the composition is acontrolled-release composition that provides release of one or moreactive ingredient(s) over a period of time, for example, at least about2 days, or at least about 7 days, or over a period of at least about 10days, or at least about 14 days, or at least about 30 days, or at leastabout 45 days, or over one month or more. Preferred embodiments includethose that release an active ingredient over 2 months or more, or threemonths or more. The components in a controlled-release composition maybe tailored according to the release time required, for example to varythe release period from about 1 month to about 6 months. In embodiments,the composition provides release of the one or more active ingredient(s)over a period of at least about 1-2 days, 1-7 days, 1-10 days, 1-14days, 1-30 days, 2-7 days, 2-days, 2-14 days, 2-30 days, 7-10 days, 7-14days, 7-30 days, 14-30 days, 30-45 days, or more. In other embodiments,the composition provides release of the one or more active ingredient(s)over a period of at least about one week, two weeks, three weeks, onemonth, six months or more. In further embodiments, the compositionprovides release of the one or more active ingredient(s) over a periodof at least about 1 month, 2 months, 3 months, 4 months, 5 months, 6months, 9 months, 12 months, or more. It will be appreciated that theperiod of release may be provided by administration of the furthercompositions.

In another embodiment, the compositions provide for immediate release ofthe therapeutic or active agent(s), such as an anti-fungal agent. In oneembodiment, the agent is released from the composition within about 10minutes-2 hours after administration, preferably within about 10minutes-1 hour, or 10 minutes-30 minutes after administration.Subsequent immediate release compositions can be administered at anydesired interval, and can also be administered in conjunction withcompositions that provide for an extended release of the agent, wherethe immediate release composition and an extended release compositionare administered at the same time or subsequent to each other.

The total dose delivered for the active agent may vary depending on suchfactors as the particular agent used and whether the composition isbeing administered for treatment or prophylaxis. For example, the activeagent delivered to the tissues of the nail unit in a givenadministration may be between about 10 μg and about 1 mg, or betweenabout 0.05 mg and about 0.5 mg. In some embodiments, the composition isa solid or semi-solid composition that comprises between about 0.25-1.0mg, preferably between about 0.25-0.75 mg, more preferably between about0.25-0.50 mg of an agent such as an anti-fungal agent. Determining thetotal dose of the active agent may be determined based on recommended orapproved dosages and/or studies to determine the appropriate dose.

The ability of the nail plate to store a drug is known in the art. Thus,in an embodiment of the present treatment method, compositions aredeposited periodically that take advantage of the ongoing presence ofactive ingredient in the nail plate, even after release of the activeingredient from the composition is complete. Subsequent treatment withadditional compositions may be timed to account for the ongoing presenceof active ingredient in the nail plate.

In another embodiment, the methods are used in combination withadditional therapies for the treatment of diseases of the nail unit. Forexample, a controlled release composition or composition of the presentmethod is deposited subungually or periungually and is used incombination with a topical treatment. Such combination treatments can beparticularly advantageous when treatment of both the nail bed and nailplate are required, for example, in certain forms of onychomycosis. Asan example, it is envisioned that the use of a topical lacquercontaining terbinafine hydrochloride be combined with the use of asubungually deposited controlled release subungual or periungualcomposition containing terbinafine hydrochloride for the treatment ofonychomycosis. In other embodiments, it is envisioned that oralcompositions for systemic delivery of an active ingredient be combinedwith compositions for the treatment of various diseases of the nailunit, including onychomycosis and nail psoriasis. In other embodiments,it is envisioned that suitable conventional therapies as previouslydiscussed herein for the treatment of the various diseases of the nailunit be used in combination with the compositions now to be described.

B. Composition Components

As mentioned above, a composition for use in the treatment methoddescribed herein may take varying forms, e.g., a solid, a semisolid, ora solution. The solution can be a dispersion, suspension or emulsion.The composition may be a non-temperature dependent phase changecomposition. The composition may also take the form of microparticles,nanoparticles, crystals, and the like, depending on such factors as theparticular active agent used, the type of nail condition being treated,and the medical history of the patient. However, in all instances, thecomposition contains a drug load capable of delivering a therapeuticallyeffective amount of an active agent to treat a nail unit condition. By“therapeutically effective amount” it is meant an amount of active agenteffective to treat a nail unit condition. The compositions, in oneembodiment, include an active agent and a biocompatible carrier or amatrix forming material that may be a biodegradable, bioerodible, orbioabsorbable polymer. The compositions may have any suitable form, andany suitable type of release, e.g., they may be configured for sustainedrelease or immediate release.

When a solution, the composition is preferably an injectable liquid.Solutions with dissolved or dispersed active agent may be formulated todeliver a large amount of active agent in a small volume, e.g., about 10μL to about 250 μL or about 50 μL to about 100 μL. Generally, anysolvent that is suitable for injection into tissue may be used. Solventsthat may be beneficial for these solutions include without limitation,water, oils, such as silicone oil, sesame oil, corn oil and the like,ethanol, dimethyl sulfoxide (DMSO), N-methylpyrrolidone, orN,N-dimethylacetamide, polyethylene glycol 400 or polyethylene glycol600. A surfactant may be beneficial for use with these solutions, e.g.,a polysorbate such as polysorbate 80 (Tween-80). Adjustment of the pH ofthe solution may also be beneficial to enhance the solubility of theactive. For active agents that exist in a salt form, the liquidformulation may comprise the salt form of the active and or the freebase form of the active. Where the active agent may exist in a liquidform at room temperature, e.g., the un-ionized or free base form ofterbinafine, the liquid composition may comprise up to and including100% active agent.

In one embodiment, the active is preferably present in about 0.1 wt. %to about 50 wt. % of the solution composition. In other embodiments, theactive is preferably present in about 0.1 wt. % to about 30 wt. %, morepreferably from about 1 wt. % to about 30 wt. %, even more preferablyfrom about 5 wt. % to about 25 wt. %, of the composition. In otherembodiments, the composition, whether a solution or semi-solid,comprises between about 0.1-25 percent by weight of the active such asan anti-fungal agent, more preferably between about 0.5-20 or 0.5-5percent by weight.

A composition in the form of a solution can generally be injected with aneedle or cannula having a gauge of 18 or 19 or higher, more preferably20 or higher, or 25 or higher, or 30 or higher. In one embodiment, theneedle or cannula has a gauge of at least about 18-30 or higher. Inother embodiments, the needle or cannula has a gauge of at least about18-25 or higher. The gauge of the needle or cannula is selected suchthat the composition may flow through the needle or cannula into thesubungual or periungual space, while at the same time minimize localtrauma and discomfort in the subject. In one, non-limiting embodiment,an 18 gauge blunt tip cannula is inserted into the subungual space whichcreates a channel or space in the subungual space. The cannula isremoved and an 18 gauge or 25 gauge needle is inserted at leastpartially into the channel or space created by the cannula. Acomposition is inserted into the channel or space and the needle iswithdrawn.

In a preferred embodiment, the solution composition remainssubstantially deposited subungually or periungually upon withdrawal ofthe needle or cannula. In another embodiment, the composition to beinjected comprises a flowable gel, a suspension or a solution, comprisedof the active agent and a liquid carrier, such as an oil or otherhydrophobic solvent. In one embodiment, the oil is a silicone oil.

A solid composition may be comprised of only one or more drug or agentor may be comprised of one or more drug or agent dispersed in abiocompatible carrier or matrix material. The carrier or matrix materialmay be any biocompatible polymeric or nonpolymeric material. Thebiocompatible materials may also be biodegradable, bioerodible, orbioabsorbable, and some examples are listed below.

The solid compositions may include at least about 30% by weight of anactive agent, at least about 50% by weight of an active agent, or insome instances, at least about 75% by weight of an active agent. In oneembodiment, the composition is comprised of a biodegradable polymer. Inanother embodiment, the biodegradable implant is a solid implantcomprised of a polymer having a melting temperature (Tm) greater thanthe temperature of the nail bed. In one embodiment, the composition is a“non-temperature dependent phase change composition,” which refers to acomposition that does not undergo a phase transition, e.g., a transitionbetween the solid, semi-solid, and liquid phases, due to a change intemperature.

In one embodiment, the composition is a solid and comprises at least oneactive agent generally dispersed in a biocompatible carrier or matrixmaterial. The carrier or matrix material may be any biocompatiblepolymeric or nonpolymeric material. The biocompatible materials may alsobe biodegradable, bioerodible, or bioabsorbable. As used herein, theterm “biocompatible” refers to a carrier or matrix material that doesnot cause significant tissue irritation at the target site. The term“biodegradable” refers to carrier or matrix material that degrades overtime by enzymatic or hydrolytic action, or other mechanism at the targetsite. By “bioerodible,” it is meant that the carrier or matrix materialerodes or degrades over time by contact with surrounding tissue fluids,through cellular activity or other physiological degradation mechanisms.By “bioabsorbable,” it is meant that the carrier or matrix materialbreaks down and is absorbed by a cell, tissue, or other physiologicmechanism. In another embodiment, the composition is a solid andcomprises at least one active agent coated by a biocompatible material.The coating material may be a material as described with reference to acarrier or matrix material or may be a biocompatible coating material asknown in the art.

Selection of the composition components will vary depending on thedesired release kinetics, formulation constraints, the nature of thecondition to be treated, and the like. Polymer characteristics that areconsidered include, but are not limited to, compatibility with theactive agent of interest and processing temperatures. The biocompatiblepolymer matrix usually comprises less than about 70, less than about 65,less than about 60, less than about 55, less than about 50, less thanabout 45, less than about 40, less than about 35, less than about 30,less than about 25, less than about 20, less than about 15, less thanabout 10, less than about 5, less than about 2.5, or about zero weightpercent of the composition. In one variation, the biocompatible polymercomprises about zero percent by weight of implant composition. Inanother variation, the biocompatible polymer matrix comprises about 30%by weight of the implant.

Biocompatible polymers may be employed include, but are not limited to,poly(lactide)s; poly(glycolide)s; poly(lactide-co-glycolide)s;poly(lactic acid)s; poly(glycolic acid)s; poly(lactic acid-co-glycolicacid)s; poly(caprolactone)s; poly(orthoester)s; poly(phosphazene)s;poly(phosphoester)s; poly(hydroxybutyrate)s or copolymers includingpoly(hydroxybutyrate); poly(lactide-co-caprolactone)s; polycarbonates;polyesteramides; polyanhidrides; poly(dioxanone)s; poly(alkylenealkylate)s; copolymers of polyethylene glycol and a polyorthoester;biodegradable polyurethanes; poly(amino acid)s; polyetheresters;polyacetals; polycyanoacrylates; polyvinyl alcohol);poly(oxyethylene)/poly(oxypropylene) copolymers; or blends, copolymers,and mixtures thereof.

In one variation, copolymers of glycolic and lactic acid are used. Thepercent of each monomer in poly(lactic-co-glycolic)acid (PLGA) copolymermay be 0-100%, about 15-85%, about 25-75%, or about 35-65%. If desired,a 50/50 PLGA copolymer may be employed. End-capped (e.g., acid-capped orester-capped) or uncapped PLGA, or a combination of the two forms mayalso be used.

Other components that may be used alone or in combination with thebiocompatible polymers mentioned above to form an implant, include, butare not limited to, polyethylene glycol (PEG), vitamin E and itsderivatives, dimethyl sulfone (MSM), carbamide, and blends and mixturesthereof.

In one embodiment, the composition is comprised of a polyethylene glycolwith a molecular weight of between 1,000-8,000 Daltons, more preferablybetween 2,000-5,000 Daltons, still more preferably of between2,500-4,000 Daltons, and in one embodiment is 3,500 Daltons. In theseembodiments, the composition may be comprised of one or more activeagents such as an antifungal agent distributed within a polyethyleneglycol. The composition may comprise less than about 40 weight percentpolyethylene glycol, preferably less than about 30 weight percentpolyethylene glycol, still more preferably 25 weight percent or lesspolyethylene glycol. The composition may comprise at least about 60weight percent, at least about 65 weight percent, at least about 70weight percent, at least about 75 weight percent or at least about 80weight percent of the active agent. In one embodiment, the compositioncomprises between about 70-80 weight percent active agent,alternatively, between about 65-85 weight percent active agent.

When formulated as a semisolid, the composition will usually be asemisolid emulsion, a gel, a cream, an ointment, a lotion or a paste.Semisolid emulsions are either oil-in-water or water-in-oil emulsions.Gels are typically suspension-type systems. Single-phase gels containgelling agents distributed substantially uniformly throughout thecarrier liquid, which is typically aqueous, but which may also containan alcohol and, optionally, an oil. Examples of gelling agents that maybe used include, but are not limited to, crosslinked acrylic acidpolymers such as the carbomer family of polymers, e.g.,carboxypolyalkylenes that may be obtained commercially under theCARBOPOL trademark; hydrophilic polymers such as polyethylene oxides,polyoxyethylene-polyoxypropylene copolymers, and polyvinylalcohol;cellulosic polymers such as hydroxypropyl cellulose, hydroxyethylcellulose, hydroxypropyl methylcellulose, hydroxypropyl methylcellulosephthalate, hydroxypropyl methylcellulose acetate-succinate, and methylcellulose; gums such as tragacanth and xanthan gum; sodium alginate; andgelatin. In order to prepare a uniform gel, dispersing agents such asalcohol or glycerin can be added, or the gelling agent can be dispersedby trituration, mechanical mixing or stirring, or combinations thereof.Pastes are semisolid dosage forms in which the active agent is suspendedin a suitable base. Depending on the nature of the base, pastes aredivided between fatty pastes or those made from single-phase aqueousgels. The base in a fatty paste is generally petrolatum, hydrophilicpetrolatum or the like. The pastes made from single-phase aqueous gelsgenerally incorporate carboxymethylcellulose or the like as a base.

The compositions may also take the form of a semi-solid or a liquid thatsolidifies after implantation. Solidification may occur due totemperature changes after implantation or to diffusion of a solvent outof the composition into the surrounding tissue.

In general, the volume of the composition delivered will be small. Forexample, when solutions are delivered, volumes less than about 500 μL,less than about 400 μL, less than about 300 μL, less than about 200 μL,or less than about 100 μL may be implanted (e.g., by injection). Forsolids, generally less than about 100 μL, and in some instances, lessthan about 10 μL, may be used. In some variations, volumes betweengreater than about 0 μL and about 5 μL may be employed. Given thesesmall volumes, fine gauge needles or cannulas will generally be used todeliver the compositions. For example, 19 gauge, 21 gauge, 23 gauge, 25gauge, 26 gauge, 27 gauge, 28 gauge, 29 gauge, or 30 gauge needles orcannulas may be used.

The compositions described here may be delivered in any size, shape,and/or volume compatible with the site of implantation, as long as theyhave the desired drug loading and release kinetics, and deliver anamount of active agent that is therapeutic for the intended nailcondition. For example, the solid compositions may be formed asparticles, sheets, discs, filaments, rods, and the like. The solidcompositions may be formed to have volumes between greater than 0 mm³ toabout 20 mm³, between greater than about 0 mm³ to about 10 mm³, orbetween about 1 mm³ to about 20 mm³. In some instances, the solidcompositions may be formed to have a volume of greater than about 0 mm³to about 1 mm³. However, in some variations, the volume may be greaterthan 20 mm³.

As the subungual space is limited and may be at least partly occluded,consideration may be given to the volume dispensed and the presence orconcentration of volatile and/or irritating excipients. The degree ofdisease presentation (e.g. extent of onycholysis and/or subungualhyperkeratosis, and whether the nail plate is intact or complete) mayaffect the volume of composition that is delivered. Additionally, volumeof composition that may be delivered may be affected or controlled byother treatment to the nail unit or other preparation of the nail unit.Exemplary treatments and/or preparations that may affect the volume ofcomposition that may be delivered include, but are not limited to,preparation of the nail unit by the patient or health care professional(e.g. debridement, cutting back of the nail, pretreatment withkeratolytic agent such as urea or salicylic acid).

The volume of a liquid or semi-solid product or composition may belimited by the volume of a channel created by insertion of the needleand/or cannula. The channel created by the cannula/needle and theresulting volume made available for administration of the compositionmay be estimated by considering the outside diameter of the cannula orneedle and the depth of insertion past the hyponychium. The volume for asolid product or composition may be limited by the inside diameter ofthe cannula/needle as the solid must fit within the cannula/needle.Further, the volume for a solid product or composition may be limited bythe length of the solid product or composition. The length of the solidproduct or composition may be selected based on the length of the nailplate and/or the extent of disease, among other factors. For Table 1, alength of the solid product or composition of about 4-6 or 4-8 mm wasconsidered. The volume of a solid product or composition may further belimited by the depth of insertion and/or the length of thecannula/needle. The nail plate is typically about 15 mm or less.

Table 1 shows the approximate volume of space created by insertion of acannula (or needle) having a gauge of 30, 25, 21, and 18. In someembodiments, the volume of agent delivered may be determined,approximated, or limited by the volume of space of the cannula orneedle. It will be appreciated that the depth of insertion may be varieddepending upon the volume of agent that is to be delivered.

TABLE 1 Volume of Space (mm³) Created According to Gauge of Cannula andDepth of Insertion Gauge of Depth of Insertion (mm) Cannula 4 5 6 7 8 910 11 12 30 0.30 0.38 0.46 0.53 0.61 0.68 0.76 0.84 0.91 25 0.83 1.041.24 1.45 1.66 1.87 2.07 2.28 2.49 21 2.11 2.63 3.16 3.69 4.21 4.74 5.275.79 6.32 18 5.07 6.33 7.60 8.87 10.13 11.40 12.67 13.93 15.20

Table 2 shows the approximate volume of an implant that is positionablewithin a cannula (or needle) having a gauge of 30, 25, 21, and 18.

TABLE 2 Volume of Implant (mm³) According to Gauge of Needle and Lengthof Implant Gauge Implant Length (mm) of Needle 4 5 6 7 8 30 0.07 0.080.10 0.12 0.13 25 XXTW 0.45 0.57 0.68 0.79 0.91 21 0.79 0.99 1.18 1.381.58 18 2.14 2.67 3.21 3.74 4.28

It will be appreciated that the length of the implant may be varied toadjust the volume of the implant. Where the agent is a liquid orsemi-solid, the amount of agent may be varied by adjusting the length ofthe cannula or needle that contains the agent. The volume of agent maybe also be varied by using a larger or finer gauge cannula or needle.

As used herein, the terms “active agent”, “therapeutic agent”, “agent”,and “drug” are used interchangeably and refer to any substance used totreat conditions of the nail. The active agents generally used in thecompositions described here include, an anti-infective agent, such asantibacterial agents, antifungal agents, antiviral agents, andantiseptics. Examples of antifungal agents that may be incorporated intothe composition include, in some embodiments, azole derivatives andfungicidal allylamines. The azole derivatives include ketoconazole,fluconazole, itraconazole, voriconazole, bifonazole, clotrimazole,miconazole, econazole, butoconazole, oxiconazole, sulconazole,terconazole, liarozole, irtemazol, efinaconazole, and luliconazole, aswell as substituted derivates of these such as substituted thiazole,thiadiazole, and oxadiazole. Allylamines include, without limitation,naftifine, terbinafine salts, and terbinafine free base. Otheranti-fungal agents include butenafine, tavaborole, tolnaftate,amorolfine; ciclopirox; flucytosine; griseofulvin; haloprogrin;potassium iodide sodium pyrithione; undecylenic acid; polyene antifungalantibiotics such as amphotericin B and nystatin; antifungal organicacids such as benzoic acid, salicylic acid, propionic acid, caprylicacid; and derivatives and combinations thereof. Further, commercialantifungal formulations or formulations for treatment of skin infections(e.g. tinea pedis) may be used for subungual delivery using the methodsdescribed herein. Commercial formulations include a variety of solutionsand semi-solid (creams, ointments, etc.). In embodiments, theconcentration of active agent and/or excipients may be adjusted forsubungual delivery. Exemplary commercial formulations include, but arenot limited to butenafine HCl 1% (cream, solution), clotrimazolecombinations (cream, solution, gel), ciclopirox olamine 1% (cream orlotion), ketoconazole (cream, liquid), miconazole nitrate, mycostatin(cream), naftifine HCl 1% (cream, gel), oxiconazole nitrate (cream),terbinafine HCl 1% (cream, solution, spray, patch), terbinafine oncedaily (Lamisil Once), tolnaftate (cream, spray, liquid), sulconazole(cream, solution). Further products for topical treatment of the nailunit that may be used for subungual delivery include ciclopirox/Penlac,amorolfine/Loceryl, efinaconazole, luliconazole 10% (solution), NM100060and tavobarole.

The choice of a particular antifungal agent will be readily apparent tothose skilled in the art. For example, dermatophyte onychomycosis may betreated by an antifungal agent effective against dermatophytes, such asterbinafine. As another example, a case of onychomycosis of uncertainfungal etiology may be treated with a broad-spectrum antifungal agenteffective against dermatophytes, nondermatophyte molds, and yeasts, suchas itraconazole.

In other embodiments, the active agents generally used in thecompositions described herein include antipsoriatic agents generally andagents for use in treating psoriatic nail disease in particular.Examples of antipsoriatic agents that may be incorporated into thecomposition include, in some embodiments, corticosteroids, salicyclicacid, vitamin D analogs and derivatives, retinoids and derivativesthereof, antimetabolites, and immunosuppressants/calcineurin inhibitors.Suitable corticosteroids include any of the topical corticosteroids suchas betamethasone dipropionate, clobetasol, and triamcinolone acetonide.Suitable vitamin D analogs include, but are not limited to calcipitriol,calcipotriene, tacalcitol, and calcitriol. Suitable retinoids orretinoid derivatives include, but are not limited to tazarotene. Onesuitable antimetabolite is 5-fluorouracil. One suitableimmunosuppressant is pimecrolimus.

When the composition is in the form of a solid, to form an implant, theactive agent may constitute from greater than about 30%, from greaterthan about 35%, from greater than about 40%, from greater than about45%, from greater than about 50%, from greater than about 55%, fromgreater than about 60%, from greater than about 65%, from about 70%,from greater than about 75%, from greater than about 80%, from greaterthan about 85%, from greater than about 90%, from greater than about95%, or about 100% by weight of the implant. In one variation, theactive agent comprises greater than 100% of the implant. Drug loadingmay be varied to achieve high initial drug release (burst release). Inone embodiment, the active agent comprises about 70% by weight of theimplant. In one embodiment, the antifungal agent is terbinafinehydrochloride or is terbinafine free base. In another embodiment, theagent is released by erosion or degradation of the polymer over a periodof at least about 2 weeks, alternatively over a period of at least about4 weeks.

In one embodiment, the agent is released to provide an initial burst ofagent followed by a period of extended release of agent. In oneembodiment, the period of extended release comprises at least about 10days, preferably at least about 2 weeks, more preferably at least about4 weeks.

In yet another embodiment, the active ingredient used in the methods andimplants may comprise more than one active ingredient. For example, theactive ingredient may comprise a combination of active ingredients thatdemonstrate an additive or synergistic effect. Methods to determine suchcombinations are well-known to those of skill in the art.

III. Examples

The following examples are illustrative in nature and are in no wayintended to be limiting.

Example 1 Exemplary Solid Implant

A terbinafine implant is made by mixing terbinafine HCl 1 andpolyethylene glycol, molecular weight 3350 Daltons, in a ratio of 80:20respectively (total weight of the mixture is 20 g). The mixture isfilled into a batch extruder and heated for one hour at 100° C. The meltis then extruded through a circular orifice to create a filament havinga diameter of about 0.4 mm. From the filament, various length subunitsare cut to form individual implants.

Example 2 Exemplary Solution

An aqueous solution of terbinafine HCl is reacted with sodium hydroxideat a pH of 7.5 to 13.0 to form the free base form of the drug. The freebase form is separately isolated and mixed with a silicon oil to form aflowable composition that can be administered as an implant.

Example 3 Subungual Insertion of Cannula and Needle

A subject diagnosed with onychomycosis and exhibitingonycholysis/subungual hyperkeratosis of the distal-central area of thehallux nail underwent subungual insertion of a 25 gauge needle on dayone. The nail length of the hallux was 12 mm and 9 mm of the nail wasinvolved. The needle was inserted into the space between the nail bedand the nail plate created by the onycholysis in the direction from thehyponychium toward the lunula without anesthesia. Insertion was betweenthe midline of the nail plate and the lateral nail fold. The subjectreported slight pain during the procedure as a 0.6 on a pain scale of 0to 10 (0 being no pain, 10 being the worst pain). At 18 hourspost-procedure, the subject reported pain as a zero on the pain scale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 6.5 mm todefine a subungual channel. The X-ray image as shown in FIG. 4A showsplacement of the cannula in the subungual space. The cannula waswithdrawn and an 18 gauge needle was inserted 8 mm into and beyond thechannel. The X-ray image as shown in FIG. 4B shows placement of theneedle in the subungual channel. The entire second procedure wasperformed without anesthesia. The patient reported pain during thesecond procedure as a zero on the pain scale. Insertion of a 25 gaugeneedle on the first day resulted in slight pain. Insertion of a muchlarger 18 gauge blunt tip cannula followed by insertion of an 18 gaugeneedle resulted in no pain. Thus, insertion of an 18 gaugecannula/needle was performed without causing pain.

Example 4 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibitedonycholysis/subungual hyperkeratosis primarily of the lateral aspect ofthe hallux nail. The nail length was 13 mm and 10 mm of the nail wasinvolved. The subject underwent subungual insertion of an 18 gaugecannula on day one. The needle was inserted into the space between thenail bed and the nail plate created by the onycholysis/subungualhyperkeratosis in the direction from the hyponychium toward the lunulawithout anesthesia. Insertion was between the midline of the nail plateand the lateral nail fold. The subject reported pain during theprocedure as a 3.1 on the pain scale. At 18 hours post-procedure, thesubject reported pain as a 2.2 on the pain scale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 6.5 mm todefine a subungual channel. The cannula was withdrawn and an 18 gaugeneedle was inserted 9 mm into and beyond the channel. The entire secondprocedure was performed without anesthesia. The patient reported painduring the second procedure as a 4.4 on the pain scale.

Example 5 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibited subungualhyperkeratosis of the central and lateral aspects of the distal ¾+ ofthe hallux nail. The nail length was 12.5 mm and 9 mm of the nail wasinvolved. The subject underwent subungual insertion of an 18 gaugecannula on day one without anesthesia as described in Example 4. Thesubject reported pain during the procedure as a 0.4 on the pain scale.At 18 hours post-procedure, the subject reported pain as a 0 on the painscale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 6 mm todefine a subungual channel. The cannula was withdrawn and an 18 gaugeneedle was inserted 7 mm into and beyond the channel. The entire secondprocedure was performed without anesthesia. The patient reported painduring the second procedure as a 0.2 on the pain scale.

Example 6 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibited a thickenednail plate and very dense subungual hyperkeratosis of the hallux nail.The nail length was 13 mm with the entire nail, including matrix/lunulainvolved. The subject underwent subungual insertion of an 18 gaugecannula on day one as described in Example 4. The subject reported painduring the procedure as a 9 on the pain scale and was administered adigital block anesthesia. At 18 hours post-procedure, the subjectreported pain as a 6.2 on the pain scale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 5.5 mm.The cannula was withdrawn and an 18 gauge needle was inserted 11 mm intoand beyond the channel. The entire second procedure was performedwithout anesthesia. The patient reported pain during the secondprocedure as a 4.2 on the pain scale. The example demonstrates that inpatients with a thick adherent nail and dense subungual hyperkeratosisinvolving all or most of the nail, creating of an initial channel with acannula may require the use of an anesthetic procedure to minimize pain.Once the channel has been formed, subsequent access with acannula/needle may be achieved without anesthesia and with significantlyreduced pain.

Example 7 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibited prominentsubungual hyperkeratosis of both lateral aspects of the hallux nail. Thenail length was 12 mm and 8 mm of the nail was involved. The subjectunderwent subungual insertion of an 18 gauge cannula on day one withoutanesthesia as described in Example 4. The subject reported pain duringthe procedure as a 1 on the pain scale. At 18 hours post-procedure, thesubject reported pain as a 0 on the pain scale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 9.5 mm todefine a subungual channel. The cannula was withdrawn and an 18 gaugeneedle was inserted 11.5 mm into and beyond the channel. The entiresecond procedure was performed without anesthesia. The patient reportedpain during the second procedure as a 1.1 on the pain scale. Use of acannula prior to insertion of the needle resulted in similar pain forsubungual insertion of a cannula alone.

Onychomycosis exhibiting lateral edge nail involvement has been reportedto have a poor prognosis in response to systemic antifungal agents,presumably due to poor drug access to the site(s) of infection. Patientspresenting with this pattern of involvement are also frequently excludedfrom studies with topical antifungal agents. This example demonstratesthe ability of a cannula/needle to access infection sites directly withminimal pain by circumventing systemic delivery and circumnavigating thenail plate.

Example 8 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibited yellow streaksand onycholysis/hyperkeratosis primarily in the distal-central aspect ofthe hallux nail. The nail length was 9 mm and the entire nail length wasinvolved. The subject underwent subungual insertion of an 18 gaugecannula on day one without anesthesia as described in Example 4. Thesubject reported pain during the procedure as a 1 on the pain scale. At18 hours post-procedure, the subject reported pain as a 1 on the painscale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually insertedsubungually to the midline 7 mm to define a subungual channel. Thecannula was withdrawn and an 18 gauge needle was inserted 8 mm into andbeyond the channel. The entire second procedure was performed withoutanesthesia. The patient reported pain during the second procedure as a0.1 on the pain scale. Although the adherence of the nail plate to thebed is typically very tight in the midline area of the nail, theonycholysis and subungual hyperkeratosis allows for cannula/needleinsertion with minimal pain.

Example 9 Subungual Insertion of Cannula and Needle

A subject was diagnosed with onychomycosis and exhibited moderateonycholysis/subungual hyperkeratosis of the hallux nail. The nail lengthwas 14 mm and 12 mm of the nail was involved. The subject underwentsubungual insertion of an 18 gauge cannula on day one without anesthesiaas described in Example 4. The subject reported pain during theprocedure as a 0.1 on the pain scale. At 18 hours post-procedure, thesubject reported pain as a 0.3 on the pain scale.

On day two, the subject underwent a second procedure on the same nail.An 18 gauge cannula with a blunt tip was subungually inserted 11.5 mm todefine a subungual channel. The cannula was withdrawn and an 18 gaugeneedle was inserted 12.5 mm into and beyond the channel. The entiresecond procedure was performed without anesthesia. The patient reportedpain during the second procedure as a 0.3 on the pain scale.

This example demonstrates that with the cannula/needle proceduredescribed, subungual delivery even beyond the area of diseaseinvolvement may be achieved without anesthesia and with minimal pain.

While a number of exemplary aspects and embodiments have been discussedabove, those of skill in the art will recognize certain modifications,permutations, additions and sub-combinations thereof. It is thereforeintended that the following appended claims and claims hereafterintroduced are interpreted to include all such modifications,permutations, additions and sub-combinations as are within their truespirit and scope.

It is claimed:
 1. A method for treating onychomycosis, comprising:determining an insertion point for insertion of an instrumentsubungually between a nail plate and a nail bed in a nail unit of asubject with onychomycosis; identifying a visible proximal edge offungal infection in the nail unit of the subject; and administering, byinsertion at the insertion point to deposit at approximately the visibleproximal edge of fungal infection, a composition comprising an activeagent for treating onychomycosis.
 2. The method of claim 1, whereindetermining an insertion point comprises determining the point ofgreatest curvature of the nail plate in a region defined by alongitudinal midline of the nail plate and a lateral nail fold.
 3. Themethod of claim 1, wherein determining an insertion point comprisesdetermining a point of onycholysis in a region defined by a longitudinalmidline of the nail plate and a lateral nail fold.
 4. The method ofclaim 1, further comprising after said determining, creating a subungualchannel by inserting a cannula at the insertion point to form asubungual channel in the nail unit.
 5. The method of claim 4, whereinthe cannula is inserted to form a subungual channel that extends fromthe insertion point to approximately the visible proximal edge of fungalinfection.
 6. The method of claim 4, wherein said administeringcomprises administering by insertion at the insertion point a needleinto the subungual channel.
 7. The method of claim 6, wherein saidadministering comprises administering the composition in the subungualchannel such that at least a portion of the composition extends beyondthe visible proximal edge of fungal infection.
 8. The method of claim 1,wherein determining comprises determining an insertion point forinsertion of an instrument selected from a blunt end cannula and aneedle.
 9. The method of claim 8, wherein the instrument is a cannula,and the method further comprises inserting the cannula at the insertionpoint to approximately the visible proximal edge of fungal infection tocreate a subungual channel.
 10. The method of claim 9, whereinadministering comprises inserting a needle into the subungual channel,wherein the composition with an active agent is placed in a tip regionof the needle.
 11. The method of claim 10, wherein said administeringcomprises administering the composition in the subungual channel suchthat at least a portion of the composition extends beyond the visibleproximal edge of fungal infection.
 12. The method of claim 4, whereinthe subungual channel extends distally from a distal edge of the nailplate to a proximal edge of fungal infection.
 13. The method of claim 4,wherein creating a subungual channel comprises debriding subungualdebris.
 14. The method of claim 4, wherein creating further comprisesdepositing an anesthetic in the subungual channel.
 15. The method ofclaim 1, wherein the composition is a solid composition, a semi-solidcomposition or a solution.
 16. The method of claim 15, wherein thecomposition is a solid or a semi-solid composition comprised of abiodegradable polymer.
 17. The method of claim 16, wherein thebiodegradable polymer is polyethylene glycol.
 18. The method of claim 1,wherein the active agent is an antifungal agent.
 19. The method of claim18, wherein the antifungal agent is terbinafine hydrochloride.
 20. Themethod of claim 19, wherein the composition comprises between about65-80 weight percent anti-fungal agent.